Immunogenicity and reactogenicity of fractional vs. full booster doses of COVID-19 vaccines: A non-inferiority, randomized, double-blind, phase IV clinical trial in Pakistan

Background: We evaluated the immunogenicity and safety of fractional doses of SARS-CoV-2 booster vaccines compared to full doses in adults aged 18–60 primed with full series of Sinovac, AZD1222, or Natural Infection in Sindh, Pakistan. Methods: This observer-blind, randomized phase IV non-inferiority trial (Feb 2023–Jan 2024) evaluated one-third, half, or full doses of BNT162b2, or full-dose Sinovac, in 10 arms based on primary vaccination. Participants were followed for 6 months with blood samples and safety assessments at days 0, 28, 84, and 182. The primary endpoint was a > 4-fold rise in anti-Spike IgG at day 28, comparing full and fractional doses using a 10% non-inferiority margin. Findings: A total of 903 participants received boosters. In Sinovac-primed individuals, ½ and ⅓ dose BNT162b2 boosters showed non-inferior seroresponse at Day 28 compared to full-dose Sinovac (66.7% and 70.5% vs. 19.4%), with higher responses at Days 84 and 182. No other non-inferiority comparisons met the threshold. Antibody levels were similar between full and fractional BNT162b2 doses over six months. All boosters were well tolerated, with no serious adverse events. Interpretation: Fractional BNT162b2 doses were non-inferior to the full Sinovac dose, but not to the full BNT162b2 dose in any priming group. Given these findings and considering the need for further research on antibody thresholds to fully understand the protection provided by fractional doses, we recommend using full BNT162b2 doses as boosters for those primed with Sinovac. If full BNT162b2 doses are not available, fractional BNT162b2 doses may be considered, but another Sinovac dose should be avoided.